Open AccessIdentification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma
Author(s) -
Nakamura Yohko,
Suganami Akiko,
Fukuda Mayu,
Hasan Md. Kamrul,
Yokochi Tomoki,
Takatori Atsushi,
Satoh Shunpei,
Hoshino Tyuji,
Tamura Yutaka,
Nakagawara Akira
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.175
Subject(s) - tropomyosin receptor kinase b , in silico , tunel assay , neuroblastoma , brain derived neurotrophic factor , virtual screening , apoptosis , pharmacology , cancer research , in vivo , docking (animal) , neurotrophic factors , biology , chemistry , receptor , bioinformatics , cell culture , medicine , drug discovery , biochemistry , genetics , gene , nursing
Neuroblastoma ( NB ) is one of the most frequent solid tumors in children and its prognosis is still poor. The neurotrophin receptor TrkB and its ligand brain‐derived neurotrophic factor (BDNF) are expressed at high levels in high‐risk NB s and are involved in defining the poor prognosis of the patients. However, the TrkB targeting therapy has never been realized in the clinic. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF ‐binding domain of TrkB. For the first screening, a library of three million synthetic compounds was screened in silico and was ranked according to the Docking energy. The top‐ranked 37 compounds were further functionally screened for cytotoxicity by using NB cell lines. We have finally identified seven compounds that kill NB cells with the IC 50 values of 0.07–4.6 μ mol/L. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion, and colony formation, possibly suggesting competition at the BDNF ‐binding site of TrkB. The candidate compounds had tumor‐suppressive activity in xenograft and in vivo toxicity tests (oral and intravenous administrations) using mice, and did not show any abnormal signs. Using in silico Docking screening we have found new candidate TrkB inhibitors against high‐risk NB s, which could lead to new anti‐cancer drugs.